Please note: this site relies heavily on the use of javascript.
Without a javascript-enabled browser, this site will not function correctly.
Please enable javascript and reload the page, or switch to a different browser.

The Wikipedia text that you see displayed here is a download
from Wikipedia. This means that the information
we display is a copy of the information from the Wikipedia
database. The button next to the article title ("Edit
Wikipedia article") takes you to the edit page for the
article directly within Wikipedia. You should be aware you
are not editing our local copy of this information. Any
changes that you make to the Wikipedia article will not be
displayed here until we next download the article from
Wikipedia. We currently download new content on a nightly
basis.

Does Pfam agree with the content of the Wikipedia entry ?

Pfam has chosen to link families to Wikipedia articles. In
some case we have created or edited these articles but in
many other cases we have not made any direct contribution to
the content of the article. The Wikipedia community does
monitor edits to try to ensure that (a) the quality of
article annotation increases, and (b) vandalism is very
quickly dealt with. However, we would like to emphasise that
Pfam does not curate the Wikipedia entries and we cannot
guarantee the accuracy of the information on the Wikipedia
page.

Editing Wikipedia articles

Before you edit for the first time

Wikipedia is a free, online encyclopedia. Although anyone can
edit or contribute to an article, Wikipedia has some strong
editing guidelines and policies, which promote the Wikipedia
standard of style and etiquette. Your edits and contributions
are more likely to be accepted (and remain) if they are in
accordance with this policy.

How your contribution will be recorded

Anyone can edit a Wikipedia entry. You can do this either as
a new user or you can register with Wikipedia and log on.
When you click on the "Edit Wikipedia article"
button, your browser will direct you to the edit page for
this entry in Wikipedia. If you are a registered user and
currently logged in, your changes will be recorded under your
Wikipedia user name. However, if you are not a registered
user or are not logged on, your changes will be logged under
your computer's IP address. This has two main implications.
Firstly, as a registered Wikipedia user your edits are more
likely seen as valuable contribution (although all edits are
open to community scrutiny regardless). Secondly, if you
edit under an IP address you may be sharing this IP address
with other users. If your IP address has previously been
blocked (due to being flagged as a source of 'vandalism')
your edits will also be blocked. You can find more
information on this and creating a
user account at Wikipedia.

Caspases are essential in cells for apoptosis, or programmed cell death, in development and most other stages of adult life, and have been termed "executioner" proteins for their roles in the cell. Some caspases are also required in the immune system for the maturation of lymphocytes. Failure of apoptosis is one of the main contributions to tumour development and autoimmune diseases; this, coupled with the unwanted apoptosis that occurs with ischemia or Alzheimer's disease, has stimulated interest in caspases as potential therapeutic targets since they were discovered in the mid-1990s.

Contents

Types of caspase proteins

As of November 2009[update], twelve caspases have been identified in humans.[3] There are two types of apoptotic caspases: initiator (apical) caspases and effector (executioner) caspases. Initiator caspases (e.g., CASP2, CASP8, CASP9, and CASP10) cleave inactive pro-forms of effector caspases, thereby activating them. Effector caspases (e.g., CASP3, CASP6, CASP7) in turn cleave other protein substrates within the cell, to trigger the apoptotic process. The initiation of this cascade reaction is regulated by caspase inhibitors.

CASP4 and CASP5, which are overexpressed in some cases of vitiligo and associated autoimmune diseases caused by NALP1 variants,[4] are not currently classified as initiator or effector in MeSH,[5] because they are inflammatory enzymes that, in concert with CASP1, are involved in T-cell maturation.

Caspase cascade

Caspases are regulated at a post-translational level, ensuring that they can be rapidly activated. They are first synthesized as inactive pro-caspases, that consist of a prodomain, a small subunit and a large subunit. Initiator caspases possess a longer prodomain than the effector caspases, whose prodomain is very small. The prodomain of the initiator caspases contain domains such as a CARD domain (e.g., caspases-2 and caspase-9) or a death effector domain (DED) (caspases-8 and caspase-10) that enables the caspases to interact with other molecules that regulate their activation. These molecules respond to stimuli that cause the clustering of the initiator caspases. Such clustering allows them to activate automatically, so that they can proceed to activate the effector caspases.

The role of caspase substrate cleavage in the morphology of apoptosis is not clear. However, ICAD/DFF45 acts to restrain CAD (caspase-activated DNase). The cleavage and inactivation of ICAD/DFF45 by a caspase allows CAD to enter the nucleus and fragment the DNA, causing the characteristic 'DNA ladder' in apoptotic cells.

Discovery of caspases, functions

H. Robert Horvitz initially established the importance of caspases in apoptosis and found that the ced-3 gene is required for the cell death that took place during the development of the nematodeC. elegans. Horvitz and his colleague Junying Yuan found in 1993 that the protein encoded by the ced-3 gene is cysteine protease with similar properties to the mammalian interleukin-1-beta converting enzyme (ICE) (now known as caspase 1), which at the time was the only known caspase.[6] Other mammalian caspases were subsequently identified, in addition to caspases in organisms such as fruit fly Drosophila melanogaster.

Researchers decided upon the nomenclature of the caspase in 1996. In many instances, a particular caspase had been identified simultaneously by more than one laboratory, who would each give the protein a different name. For example, caspase 3 was variously known as CPP32, apopain and Yama. Caspases, therefore, were numbered in the order in which they were identified.[2] ICE was, therefore, renamed as caspase 1. ICE was the first mammalian caspase to be characterised because of its similarity to the nematode death gene ced-3, but it appears that the principal role of this enzyme is to mediate inflammation rather than cell death.

For the discovery of caspases and other aspects of apoptosis, see articles by Danial and Korsmeyer,[7] Yuan and Horvitz,[8] and by Li et al.[9] in the January 23, 2004 edition of the journal Cell.

Recent studies have demonstrated that caspase proteases are also regulators of non-death functions, the most notable ones being those involving the maturation of a wide variety of cells such as red blood cells and skeletal muscle myoblasts.[10]

External links

Apoptosis Video Demonstrates a model of a caspase cascade as it occurs in vivo.

The Mechanisms of Apoptosis Kimball's Biology Pages. Simple explanation of the mechanisms of apoptosis triggered by internal signals (bcl-2), along the caspase-9, caspase-3 and caspase-7 pathway; and by external signals (FAS and TNF), along the caspase 8 pathway. Accessed 25 March 2007.

This tab holds the annotation information that is stored in the Pfam
database. As we move to using Wikipedia as our main source of annotation,
the contents of this tab will be gradually replaced by the Wikipedia
tab.

In the MEROPS database peptidases and peptidase homologues are grouped into clans and families. Clans are groups of families for which there is evidence of common ancestry based on a common structural fold:

Each clan is identified with two letters, the first representing the catalytic type of the families included in the clan (with the letter 'P' being used for a clan containing families of more than one of the catalytic types serine, threonine and cysteine). Some families cannot yet be assigned to clans, and when a formal assignment is required, such a family is described as belonging to clan A-, C-, M-, N-, S-, T- or U-, according to the catalytic type. Some clans are divided into subclans because there is evidence of a very ancient divergence within the clan, for example MA(E), the gluzincins, and MA(M), the metzincins.

Peptidase families are grouped by their catalytic type, the first character representing the catalytic type: A, aspartic; C, cysteine; G, glutamic acid; M, metallo; N, asparagine; S, serine; T, threonine; and U, unknown. The serine, threonine and cysteine peptidases utilise the amino acid as a nucleophile and form an acyl intermediate - these peptidases can also readily act as transferases. In the case of aspartic, glutamic and metallopeptidases, the nucleophile is an activated water molecule. In the case of the asparagine endopeptidases, the nucleophile is asparagine and all are self-processing endopeptidases.

In many instances the structural protein fold that characterises the clan or family may have lost its catalytic activity, yet retain its function in protein recognition and binding.

Cysteine peptidases have characteristic molecular topologies, which can be seen not only in their three-dimensional structures, but commonly also in the two-dimensional structures. These are peptidases in which the nucleophile is the sulphydryl group of a cysteine residue. Cysteine proteases are divided into clans (proteins which are evolutionary related), and further sub-divided into families, on the basis of the architecture of their catalytic dyad or triad [PUBMED:11517925].

This group of sequences represent the p20 (20kDa) and p10 (10kDa) subunits of caspases, which together form the catalytic domain of the caspase and are derived from the p45 (45 kDa) precursor (INTERPRO) [PUBMED:15226512].

Caspases (Cysteine-dependent ASPartyl-specific proteASE) are cysteine peptidases that belong to the MEROPS peptidase family C14 (caspase family, clan CD) based on the architecture of their catalytic dyad or triad [PUBMED:11517925]. Caspases are tightly regulated proteins that require zymogen activation to become active, and once active can be regulated by caspase inhibitors. Activated caspases act as cysteine proteases, using the sulphydryl group of a cysteine side chain for catalysing peptide bond cleavage at aspartyl residues in their substrates. The catalytic cysteine and histidine residues are on the p20 subunit after cleavage of the p45 precursor.

Caspases are mainly involved in mediating cell death (apoptosis) [PUBMED:10578171, PUBMED:10872455, PUBMED:15077141]. They have two main roles within the apoptosis cascade: as initiators that trigger the cell death process, and as effectors of the process itself. Caspase-mediated apoptosis follows two main pathways, one extrinsic and the other intrinsic or mitochondrial-mediated. The extrinsic pathway involves the stimulation of various TNF (tumour necrosis factor) cell surface receptors on cells targeted to die by various TNF cytokines that are produced by cells such as cytotoxic T cells. The activated receptor transmits the signal to the cytoplasm by recruiting FADD, which forms a death-inducing signalling complex (DISC) with caspase-8. The subsequent activation of caspase-8 initiates the apoptosis cascade involving caspases 3, 4, 6, 7, 9 and 10. The intrinsic pathway arises from signals that originate within the cell as a consequence of cellular stress or DNA damage. The stimulation or inhibition of different Bcl-2 family receptors results in the leakage of cytochrome c from the mitochondria, and the formation of an apoptosome composed of cytochrome c, Apaf1 and caspase-9. The subsequent activation of caspase-9 initiates the apoptosis cascade involving caspases 3 and 7, among others. At the end of the cascade, caspases act on a variety of signal transduction proteins, cytoskeletal and nuclear proteins, chromatin-modifying proteins, DNA repair proteins and endonucleases that destroy the cell by disintegrating its contents, including its DNA. The different caspases have different domain architectures depending upon where they fit into the apoptosis cascades, however they all carry the catalytic p10 and p20 subunits.

Caspases can have roles other than in apoptosis, such as caspase-1 (interleukin-1 beta convertase) (EC), which is involved in the inflammatory process. The activation of apoptosis can sometimes lead to caspase-1 activation, providing a link between apoptosis and inflammation, such as during the targeting of infected cells. Caspases may also be involved in cell differentiation [PUBMED:15066636].

Gene Ontology

The mapping between Pfam and Gene Ontology is provided by InterPro.
If you use this data please
cite InterPro.

Domain organisation

Below is a listing of the unique domain organisations or architectures in which
this domain is found.
More...

The graphic that is shown by default represents the longest sequence
with a given architecture. Each row contains the following information:

the number of sequences which exhibit this architecture

a textual description of the architecture, e.g. Gla, EGF x 2, Trypsin.
This example describes an architecture with one Gla
domain, followed by two consecutive EGF domains, and
finally a single Trypsin domain

a link to the page in the Pfam site showing information about the
sequence that the graphic describes

Note that you can see the family page for a particular domain by
clicking on the graphic. You can also choose to see all sequences which
have a given architecture by clicking on the Show link
in each row.

Finally, because some families can be found in a very large number of
architectures, we load only the first fifty architectures by default.
If you want to see more architectures, click the button at the bottom
of the page to load the next set.

Loading domain graphics...

Pfam Clan

This family is a member of clan Peptidase_CD
(CL0093),
which has the following description:

The members of this clan are all endopeptidase that have the catalytic dyad histidine followed by cysteine. The catalytic histidine is preceded by a block of hydrophobic residues and a glycine, where as the cysteine is preceded by a block of hydrophobic residues and a glutamine and an alanine. The members with a know structure adopt an alpha/beta fold [1].

Alignments

We store a range of different sequence alignments for families. As well
as the seed alignment from which the family is built, we provide the
full alignment, generated by searching the sequence database using the
family HMM. We also generate alignments using four
representative proteomes (RP) sets, the NCBI sequence database,
and our metagenomics sequence database.
More...

There are various ways to view or download the sequence alignments that
we store. We provide several sequence viewers and a plain-text
Stockholm-format file for download.

Alignment types

We make a range of alignments for each Pfam-A family:

seed

the curated alignment from which the HMM for the family is
built

full

the alignment generated by searching the sequence database
using the HMM

Viewing

a Java applet developed at the University of Dundee. You will
need Java installed
before running jalview

HTML

an HTML page showing the whole alignment.Please
note: full Pfam alignments can be very large. These
HTML views are extremely large and often cause problems for browsers.
Please use either jalview or the Pfam viewer if you have trouble
viewing the HTML version

PP/Heatmap

an HTML-based representation of the alignment, coloured according to
the posterior-probability (PP) values from the HMM. As for the standard HTML
view, heatmap alignments can also be very large and slow to render.

Pfam viewer

an HTML-based viewer that uses
DAS
to retrieve alignment fragments on request

Reformatting

You can download (or view in your browser) a text representation of a
Pfam alignment in various formats:

Selex

Stockholm

FASTA

MSF

You can also change the order in which sequences are listed in the
alignment, change how insertions are represented, alter the characters
that are used to represent gaps in sequences and, finally, choose
whether to download the alignment or to view it in your browser
directly.

Downloading

You may find that large alignments cause problems for the viewers and
the reformatting tool, so we also provide all alignments in Stockholm
format. You can download either the plain text alignment, or a gzipped
version of it.

View options

We make a range of alignments for each Pfam-A family. You can see a
description of each
above.
You can view these alignments in various ways but please note that some
types of alignment are never generated while others may not be available
for all families, most commonly because the alignments are too large to
handle.

Seed(115)

Full(4033)

Representative proteomes

NCBI(4284)

Meta(706)

RP15(653)

RP35(1049)

RP55(1463)

RP75(1901)

Jalview

View

View

View

View

View

View

View

View

HTML

View

View

View

View

View

View

PP/heatmap

1

View

View

View

View

View

Pfam viewer

View

View

1Cannot generate PP/Heatmap alignments for seeds; no PP data available

Key: available,
not generated,
— not available.

Format an alignment

Seed(115)

Full(4033)

Representative proteomes

NCBI(4284)

Meta(706)

RP15(653)

RP35(1049)

RP55(1463)

RP75(1901)

Alignment:

Format:

Order:

TreeAlphabetical

Sequence:

Inserts lower caseAll upper case

Gaps:

Download/view:

DownloadView

Download options

We make all of our alignments available in Stockholm format.
You can download them here as raw, plain text files or as
gzip-compressed files.

You can also
download a FASTA format file containing the
full-length sequences for all sequences in the full alignment.

External links

MyHits provides a
collection of tools to handle multiple sequence alignments. For example,
one can refine a seed alignment (sequence addition or removal,
re-alignment or manual edition) and then search databases for remote
homologs using HMMER3.

Loading...

HMM logo

HMM logos is one way of visualising profile HMMs. Logos provide a
quick overview of the properties of an HMM in a graphical form. You can
see a more detailed description of HMM logos and find out how you can
interpret them
here.
More...

If you find these logos useful in your own work, please consider citing
the following article:

Trees

This page displays the phylogenetic tree for this family's seed
alignment. We use
FastTree
to calculate neighbour join trees with a local bootstrap based on 100
resamples (shown next to the tree nodes). FastTree calculates
approximately-maximum-likelihood phylogenetic trees from our seed
alignment.

Curation and family details

This section shows the detailed information about the Pfam family. You
can see the definitions of many of the terms in this section in the
glossary and a fuller
explanation of the scoring system that we use in the
scores section of the
help pages.

Currently selected:

This visualisation provides a simple graphical representation of
the distribution of this family across species. You can find the
original interactive tree in the
adjacent tab.
More...

This chart is a modified "sunburst" visualisation of
the species tree for this family. It shows each node in the
tree as a separate arc, arranged radially with the superkingdoms
at the centre and the species arrayed around the outermost
ring.

How the sunburst is generated

The tree is built by considering the taxonomic lineage of each
sequence that has a match to this family. For each node in the
resulting tree, we draw an arc in the sunburst. The radius of
the arc, its distance from the root node at the centre of the
sunburst, shows the taxonomic level ("superkingdom",
"kingdom", etc). The length of the arc represents
either the number of sequences represented at a given level, or
the number of species that are found beneath the node in the
tree. The weighting scheme can be changed using the sunburst
controls.

In order to reduce the complexity of the representation, we
reduce the number of taxonomic levels that we show. We consider
only the following eight major taxonomic levels:

superkingdom

kingdom

phylum

class

order

family

genus

species

Colouring and labels

Segments of the tree are coloured approximately according to
their superkingdom. For example, archeal branches are coloured
with shades of orange, eukaryotes in shades of purple, etc. The
colour assignments are shown under the sunburst controls. Where
space allows, the name of the taxonomic level will be written on
the arc itself.

As you move your mouse across the sunburst, the current node
will be highlighted. In the top section of the controls panel we
show a summary of the lineage of the currently highlighed node.
If you pause over an arc, a tooltip will be shown, giving the
name of the taxonomic level in the title and a summary of the
number of sequences and species below that node in the tree.

Anomalies in the taxonomy tree

There are some situations that the sunburst tree cannot easily
handle and for which we have work-arounds in place.

Missing taxonomic levels

Some species in the taxonomic tree may not have one or more of
the main eight levels that we display. For example, Bos
taurus is not assigned an order in the NCBI taxonomic tree.
In such cases we mark the omitted level with, for example,
"No order", in both the tooltip and the lineage
summary.

Unmapped species names

The tree is built by looking at each sequence in the full
alignment for the family. We take the name of the species given
by UniProt and try to map that to the full taxonomic tree from
NCBI. In some cases, the name chosen by UniProt does not map to
any node in the NCBI tree, perhaps because the chosen name is
listed as a synonym or a misspelling in the NCBI taxonomy.

So that these nodes are not simply omitted from the sunburst
tree, we group them together in a separate branch (or segment of
the sunburst tree). Since we cannot determine the lineage for
these unmapped species, we show all levels between the
superkingdom and the species as "uncategorised".

Sub-species

Since we reduce the species tree to only the eight main
taxonomic levels, sequences that are mapped to the sub-species
level in the tree would not normally be shown. Rather than leave
out these species, we map them instead to their parent species.
So, for example, for sequences belonging to one of the
Vibrio cholerae sub-species in the NCBI taxonomy, we
show them instead as belonging to the species Vibrio
cholerae.

Too many species/sequences

For large species trees, you may see blank regions in the outer
layers of the sunburst. These occur when there are large numbers
of arcs to be drawn in a small space. If an arc is less than
approximately one pixel wide, it will not be drawn and the space
will be left blank. You may still be able to get some
information about the species in that region by moving your mouse
across the area, but since each arc will be very small, it will
be difficult to accurately locate a particular species.

Tree controls

Annotation

Download tree

Selected sequences

(Uncheck all)

View

graphically

as an
alignment

Download

sequence accessions

sequences in FASTA format

The tree shows the occurrence of this domain across different species.
More...

Species trees

We show the species tree in one of two ways. For smaller trees we try
to show an interactive representation, which allows you to select
specific nodes in the tree and view them as an alignment or as a set
of Pfam domain graphics.

Unfortunately we have found that there are problems viewing the
interactive tree when the it becomes larger than a certain limit.
Furthermore, we have found that Internet Explorer can become
unresponsive when viewing some trees, regardless of their size.
We therefore show a text representation of the species tree when the
size is above a certain limit or if you are using Internet Explorer
to view the site.

If you are using IE you can still load the interactive tree by
clicking the "Generate interactive tree" button, but please
be aware of the potential problems that the interactive species tree
can cause.

Interactive tree

For all of the domain matches in a full alignment, we count the
number that are found on all sequences in the alignment.
This total is shown in the purple box.

We also count the number of unique sequences on which each domain is
found, which is shown in green.
Note that a domain may appear multiple times on the
same sequence, leading to the difference between these two numbers.

Finally, we group sequences from the same organism according to the
NCBI
code that is assigned by
UniProt,
allowing us to count the number of distinct sequences on which the
domain is found. This value is shown in the
pink boxes.

We use the NCBI species tree to group organisms according to their
taxonomy and this forms the structure of the displayed tree.
Note that in some cases the trees are too large (have
too many nodes) to allow us to build an interactive tree, but in most
cases you can still view the tree in a plain text, non-interactive
representation. Those species which are represented in the seed
alignment for this domain are
highlighted.

You can use the tree controls to manipulate how the interactive tree
is displayed:

show/hide the summary boxes

highlight species that are represented in the seed alignment

expand/collapse the tree or expand it to a given depth

select a sub-tree or a set of species within the tree and view
them graphically or as an alignment

save a plain text representation of the tree

Loading...

Please note: for large trees this can take some time.
While the tree is loading, you can safely switch away from this
tab but if you browse away from the family page entirely, the tree
will not be loaded.

Interactions

There are
2
interactions for this family.
More...

We determine these interactions using
iPfam,
which considers the interactions between residues in three-dimensional
protein structures and maps those interactions back to Pfam families.
You can find more information about the iPfam algorithm in the
journal article that accompanies the website.

Structures

For those sequences which have a structure in the
Protein DataBank, we
use the mapping between UniProt, PDB and Pfam coordinate
systems from the PDBe group, to allow us to map
Pfam domains onto UniProt sequences and three-dimensional protein
structures. The table below
shows the structures on which the Peptidase_C14
domain has been found. There are 455
instances of this domain found in the PDB. Note that there may be
multiple copies of the domain in a single PDB structure, since many
structures contain multiple copies of the same protein seqence.